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ZCL-278 is a selective small molecule specifically inhibiting the Cdc42-intersectin interaction, yet its in-vivo pharmacokinetic and pharmacodynamic properties against renal diseases had not been determined. Thus, our study explored the absorption, distribution and excretion of ZCL-278 as well as its pharmacological efficacy against chronic kidney disease (CKD). With the optimized detection method, absolute oral bioavailability of ZCL-278 was determined as 10.99 % in male and 17.34 % in female rats. ZCL-278 was rapidly and abundantly distributed in various tissues, especially the kidney and heart, while few excreted through urine and feces. In the adenine-induced CKD mice, the increased plasma creatinine and urea, the decreased body weight as well as the renal pathological alterations, including vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria, were significantly ameliorated after ZCL-278 administration. Moreover, ZCL-278 could also reverse the increased intensities of renal inflammation and fibrosis in the CKD mice. These results clarified the pharmacokinetics of ZCL-278 in rats and preliminarily indicated that ZCL-278 has favorable pharmacodynamic properties for CKD primed for lead development and optimization, warranting further drug development. [Display omitted] • An UPLC-MS/MS method for quantification of ZCL-278 was developed and validated. • Systemic pharmacokinetics of ZCL-278 in rats. • Renoprotection of ZCL-278 by ameliorating renal tubular injury, inflammation, and fibrosis. [ABSTRACT FROM AUTHOR]

1. Afatinib is an oral, selective tyrosine kinase inhibitor (TKI) primarily transported by P-glycoprotein (MDR1, gene code ABCB1) and breast cancer resistance protein (BCRP, gene code ABCG2). In the present study, the effects of ABCB1 and ABCG2 genetic polymorphisms on the pharmacokinetics of afatinib in healthy Chinese were investigated. 2. Blood samples from 24 healthy participants who received afatinib were used for genotyping ABCB1 (1236C>T, 2677G > T/A, 3435C>T) and ABCG2 (34G>A, 421C>A) polymorphisms. Subsequently, the association between afatinib plasma concentrations and target single-nucleotide polymorphisms (SNPs) was analyzed. 3. Among the five polymorphisms, plasma concentrations of afatinib in healthy subjects with ABCB1 1236CC–3435CC were remarkably higher than in other genotype subjects. No significant differences of afatinib exposure were found between the ABCG2 wild-type and heterozygous groups. 4. The ABCB1 genetic polymorphism influenced the plasma exposure of afatinib, and gene testing before drug administration may be useful for clinically individualized use of afatinib. Our data suggest the usefulness of afatinib pharmacogenetics in treatment optimization. [ABSTRACT FROM AUTHOR]

Cisplatin, carboplatin, and oxaliplatin are the common platinum-based anticancer drugs widely used in the chemotherapeutic treatment of solid tumors in clinic. However, the comprehensive pharmacokinetics of platinum-based anticancer drugs has not been fully understood yet. This leads to many limitations for the further studies on their pharmacology and toxicology. In this study, we conduct a systemic evaluation on the pharmacokinetics of three platinum analogues at animal and cell levels, with quantification of both total platinum and intact drugs. A detailed animal study to address and compare the different pharmacokinetic behaviors of three platinum analogues has been conducted in three biological matrices: blood, plasma, and ultrafiltrate plasma. Carboplatin showed an obviously different pharmacokinetic characteristic from cisplatin and oxaliplatin. On the one hand, carboplatin has the highest proportion of Pt distribution in ultrafiltrate plasma. On the other hand, carboplatin has the highest intact drug exposure and longest intact drug elimination time in blood, plasma, and ultrafiltrate plasma, which may explain its high hematotoxicity. Additionally, the cellular and subcellular pharmacokinetics of oxaliplatin in two colon cancer HCT-116/LOVO cell lines has been elucidated for the first time. The biotransformation of intact oxaliplatin in cells was rapid with a fast elimination, however, the generated platinum-containing metabolites still exist within cells. The distribution of total platinum in the cytosol is higher than in the mitochondria, followed by the nucleus. Enrichment of platinum in mitochondria may affect the respiratory chain or energy metabolism, and further lead to cell apoptosis, which may indicate mitochondria as another potential target for efficacy and toxicity of oxaliplatin. [ABSTRACT FROM AUTHOR]

Highlights • A new UPLC-MS/MS method was developed for determining tebipenem in human plasma. • The method was validated according to the guidelines of European Medicines Agency. • High throughput, sensitivity, and reliability were achieved. • The method was applied to a pharmacokinetic study of tebipenem in human volunteers. Abstract A rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining tebipenem (TBPM) in human plasma. Plasma samples were prepared following a single-step protein precipitation method using acetonitrile and 3-morpholinopropanesulfonic acid (MOPS, pH 7.0, 50 mM) which equal volume of plasma samples were added for stabilizing the analyte. Separation was achieved using an ACQUITY UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column. A repeated gradient program was employed for reducing the carryover effect, and the total chromatographic run time was 3.0 min. Method validation results showed TBPM was linear in its analytical range i.e. between 0.1–20 μg/mL (r2>0.99), and the lower limit of quantification (LLOQ) was 0.1 μg/mL. The intra-run and inter-run precision (coefficient of variation, CV) was within 3.81%, and the accuracy (relative error, RE) was within ± 8.56%. The carryover was restricted below 8.1%. Matrix effects were minimal, and recovery of TBPM was 90.19–95.74%. The stability of TBPM in plasma sample stored at room temperature (25 °C) for 4 h, at −20 °C for 3 days, at −80 °C for 30 days, five freeze-thaw cycles at −80 °C and processed samples at auto sampler vials (8 °C) for 24 h were within 91.11–106.33%. Finally, the validated method was successfully applied to a pharmacokinetic study of TBPM in healthy volunteers after oral administration of tebipenem pivoxil (TBPM-PI). [ABSTRACT FROM AUTHOR]

A simple LC-MS/MS method facilitated by salting-out assisted liquid-liquid extraction (SALLE) was applied to simultaneously investigate the pharmacokinetics of trans-resveratrol (Res) and its major glucuronide and sulfate conjugates in rat plasma. Acetonitrile-methanol (80:20, v/v) and ammonium acetate (10 mol L−1) were used as extractant and salting-out reagent to locate the target analytes in the supernatant after the aqueous and organic phase stratification, then the analytes were determined via gradient elution by LC-MS/MS in negative mode in a single run. The analytical method was validated with good selectivity, acceptable accuracy (>85%) and low variation of precision (<15%). SALLE showed better extraction efficiency of target glucuronide and sulfate conjugates (>80%). The method was successfully applied to determine Res and its four conjugated metabolites in rat after Res administration (intragastric, 50 mg kg−1; intravenous, 10 mg kg−1). The systemic exposures to Res conjugates were much higher than those to Res (AUC0- t, i.v., 7.43 μ m h; p.o., 8.31 μ m h); Res-3- O-β- d-glucuronide was the major metabolite (AUC0- t, i.v., 66.1 μ m h; p.o., 333.4 μ m h). The bioavailability of Res was estimated to be ~22.4%. The reproducible SALLE method simplified the sample preparation, drastically improved the accuracy of the concomitant assay and gave full consideration of extraction recovery to each target analyte in bio-samples. [ABSTRACT FROM AUTHOR]

PEGylation techniques have been increasingly employed in drug delivery system and chemical modification of compounds with low aqueous solubility. Triacontanol (TA) is a natural product with several pharmacological activities, but its low aqueous solubility significantly limited its application. PEGylated triacontanol (PEG-TA) was designed as the prodrug to improve the aqueous solubility and pharmacokinetic properties of TA. On the basis of salting-out assisted liquid-liquid extraction (SALLE) and saponification sample preparation procedure, a reliable gas chromatography tandem mass spectrometric (GC–MS/MS) method was developed and validated for the quantification of PEG-TA and its metabolite TA in rat plasma after separation and transformation. Acetonitrile-methanol (9:1, v/v) and ammonium acetate (10 M) were utilized to separate PEG-TA and TA (including conjugated TA with fatty acid). Saponification facilitated the complete conversion of PEG-TA into TA, so PEG-TA could be indirectly quantified. The results revealed that the GC–MS/MS method had excellent selectivity, accuracy and linearity. Calibration curves were linear (R 2 >0.99) within the range of 20.0–1000.0 ng/mL for TA and 100.0–10,000.0 ng/mL for PEG-TA. The intra- and inter-day precision of quality control samples were within 15%, and their accuracy values varied from 93.54% to 113.38%. This analytical method has been successfully applied to pharmacokinetic study of PEG-TA. This study can facilitate the further exploration and quantification of PEGylated prodrugs. [ABSTRACT FROM AUTHOR]